The role of IVF with PGS in recurrent miscarriage

Key questions to consider before using preimplantation genetic screening in women of advanced reproductive age.

Dr Plosker is Professor and Division Director, IVF and Reproductive Endocrinology, University of South Florida, Tampa. He has no conflicts of interest to report in respect to the content of this article.

Consequences of reproductive aging include infertility, an increased likelihood of isolated spontaneous abortion (SAB), and likely an increased likelihood of recurrent pregnancy loss (RPL).1-3 One percent to 5% of women experience RPL, which is defined as 2 or 3 consecutive clinical pregnancy losses.4 As women age, an increasing percentage of embryos are aneuploid,5,6 contributing to the increased prevalence of infertility and the increased prevalence of SAB and viable trisomies with maternal aging.

In women older than age 35 with 3 or more pregnancy losses, 70%–80% of analyzed abortuses were found to be aneuploid.3,6 Whereas aneuploidy embryos rarely implant, and those that do often end in spontaneous abortion, euploid embryos have implantation rates in the 80% range, with a 65% live birth rate.7

Preimplantation genetic screening (PGS) of embryos achieved through IVF is an intervention that can identify euploid embryos. Indeed, PGS has been used to treat RPL.8 In the absence of randomized controlled trials (RCTs) comparing IVF with PGS to expectant management in women with RPL, a thoughtful, measured approach to the application of a complex, expensive treatment is warranted.

RPL due to structural chromosome abnormalities is usually the result of aneuploidy caused by oocyte nondisjunction during meiosis I, which is an age-dependent process.5 However, in 2%–5% of couples suffering from RPL, one of the parents is found to harbor a balanced reciprocal translocation, or a Robertsonian translocation.4 According to probability theory, at least 50% of embryos created by a parent with a balanced translocation and 67% of embryos created by a parent with a Robertsonian translocation will be abnormal. In practice, the prevalence of aneuploidy or unbalanced embryos is often higher, since some reciprocal translocations are predisposed to abnormal segregation patterns, and all gamete unions are subject to a high likelihood of aneuploidy due to nondisjunction.5

When evaluating the utility of PGS in the treatment of idiopathic RPL, or in RPL associated with chromosome structural rearrangements, particularly in women of advanced reproductive age, consider:

What is the likelihood of spontaneously conceiving a live birth with a history of RPL? Brigham et al. found that 75% of women with RPL (mean 3.0 prior losses) conceived an intrauterine pregnancy, and 75% of intrauterine conceptions survived beyond 24 weeks’ gestation. This suggests a live birth rate of 56% among their cohort of 302 women. Using logistic regression, they predicted a live birth from 80% of intrauterine conceptions at age 30, 73% at age 35, and 64% at age 40.9

What is the likelihood of infertility in women of advanced reproductive age who have RPL? The cumulative 12-month pregnancy rate in women with no prior history of infertility attempting to conceive is 87%-88% in women aged 30-33, 76% in women aged 36-37, and 54% by age 40–41.1

These rates are likely to be lower in women with RPL. In women with RPL, Brigham et al. found that 25% of their cohort of women never conceived after entering the study, although they did not discern if this was due to infertility or to cessation of trying to conceive.9 This suggests that RPL due to aneuploidy may be a harbinger of infertility in older women.

How successful is IVF in women of advanced reproductive age? In 2014, national IVF live birth rates per initiated cycle were 49% in women aged younger than 35, 38% in women aged 35–37, 24% in women aged 38–40, and 12% in women aged 41–42 (SARTCORSonline.com).

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